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The multiplex interactions and molecular mechanism on genotoxicity induced by formaldehyde and acrolein mixtures on human bronchial epithelial BEAS-2B cells
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Highlights Aldehyde mixtures could induce multiplex interactions on genotoxicity. Aldehydes induced synergistic DNA/chromosome damage even at smoking-related doses. Inhibition of DNA repair enhanced synergistic DNA damage induced by aldehydes. Cytotoxicity contributed to antagonism of aldehydes on late genotoxic responses. Acrolein-induced oxidative damage dominated the DNA damage induced by mixtures.
Abstract Aldehydes are common air pollutants with carcinogenicity. Genotoxicity of single aldehyde has been studied well, but the combined genotoxicity is rarely known. Here, we evaluated the combined genotoxicity of formaldehyde and acrolein on BEAS-2B cells in terms of DNA strands breakage, chromosome damage and gene mutation below subcytotoxic concentrations covering smoking-related concentrations. Meanwhile, the molecular mechanism was investigated further based on oxidative stress, DNA-protein crosslinks (DPCs), cell cycle and DNA damage-repair pathway. Co-exposure to formaldehyde and acrolein mixtures showed significantly synergistic interaction on DNA strands breakage and chromosome damage in a concentration/time-dependent manner, while antagonism was shown on the late genotoxic endpoints (e.g. cytoplasmic block micronucleus (CBMN) and HPRT gene mutation). Moreover, formaldehyde synergistically potentiated acrolein-induced S-phase arrest, inhibition of DNA repair and up-regulation of genes related to cell stress, which conversely strengtherned mixture-induced DNA/chromosome damage and finally resulted in antagonism on late genotoxic events. Additionally, formaldehyde-induced DNA damage mainly resulted from the direct covalent bonding (e.g. DPCs), while acrolein-induced DNA damage mainly generated from oxidative damage (e.g. oxidative stress), which dominated the synergistic DNA strand breakage induced by mixtures. Summarily, aldehyde mixtures (formaldehyde and acrolein) induced multiplex combined genotoxicity on BEAS-2B cells even at smoking-related concentrations, which was dependent on genotoxic endpoints and closely related to that formaldehyde potentiated acrolein-induced cell stress, S-phase arrest and inhibition of DNA repair. So prolonged exposure to aldehyde mixtures may have a more serious risk to respiratory system in animal and human than the expectation based on the toxicity of single aldehyde even at environmentally relevant concentrations.
The multiplex interactions and molecular mechanism on genotoxicity induced by formaldehyde and acrolein mixtures on human bronchial epithelial BEAS-2B cells
Graphical abstract Display Omitted
Highlights Aldehyde mixtures could induce multiplex interactions on genotoxicity. Aldehydes induced synergistic DNA/chromosome damage even at smoking-related doses. Inhibition of DNA repair enhanced synergistic DNA damage induced by aldehydes. Cytotoxicity contributed to antagonism of aldehydes on late genotoxic responses. Acrolein-induced oxidative damage dominated the DNA damage induced by mixtures.
Abstract Aldehydes are common air pollutants with carcinogenicity. Genotoxicity of single aldehyde has been studied well, but the combined genotoxicity is rarely known. Here, we evaluated the combined genotoxicity of formaldehyde and acrolein on BEAS-2B cells in terms of DNA strands breakage, chromosome damage and gene mutation below subcytotoxic concentrations covering smoking-related concentrations. Meanwhile, the molecular mechanism was investigated further based on oxidative stress, DNA-protein crosslinks (DPCs), cell cycle and DNA damage-repair pathway. Co-exposure to formaldehyde and acrolein mixtures showed significantly synergistic interaction on DNA strands breakage and chromosome damage in a concentration/time-dependent manner, while antagonism was shown on the late genotoxic endpoints (e.g. cytoplasmic block micronucleus (CBMN) and HPRT gene mutation). Moreover, formaldehyde synergistically potentiated acrolein-induced S-phase arrest, inhibition of DNA repair and up-regulation of genes related to cell stress, which conversely strengtherned mixture-induced DNA/chromosome damage and finally resulted in antagonism on late genotoxic events. Additionally, formaldehyde-induced DNA damage mainly resulted from the direct covalent bonding (e.g. DPCs), while acrolein-induced DNA damage mainly generated from oxidative damage (e.g. oxidative stress), which dominated the synergistic DNA strand breakage induced by mixtures. Summarily, aldehyde mixtures (formaldehyde and acrolein) induced multiplex combined genotoxicity on BEAS-2B cells even at smoking-related concentrations, which was dependent on genotoxic endpoints and closely related to that formaldehyde potentiated acrolein-induced cell stress, S-phase arrest and inhibition of DNA repair. So prolonged exposure to aldehyde mixtures may have a more serious risk to respiratory system in animal and human than the expectation based on the toxicity of single aldehyde even at environmentally relevant concentrations.
The multiplex interactions and molecular mechanism on genotoxicity induced by formaldehyde and acrolein mixtures on human bronchial epithelial BEAS-2B cells
Zhang, Sen (author) / Chen, Huan (author) / Zhang, Jingni (author) / Li, Jun (author) / Hou, Hongwei (author) / Hu, Qingyuan (author)
2020-07-01
Article (Journal)
Electronic Resource
English
Formaldehyde , Acrolein , Combined effects , Genotoxicity , DNA damage-repair , FA , ACR , FAM , FA and ACR mixture , CS , Cigarette smoke , GVP , Gas vapor phase , WHO , World health organisation , FCTC , Framework convention on tobacco control , BEGM , Bronchial epithelial cell growth medium , DSBs , DNA double-strand breakages , CASP , Comet assay software project , CBMN , Cytoplasmic block micronucleus , NCBMN , Non cytoplasmic block micronucleus , DPCs , DNA-protein crosslinks , SDS , Sodium dodecyl sulfate , PMSF , Phenylmethylsulfonyl fluoride , BSA , Bovine serum albumin , SD , Standard deviation , ANOVA , Analysis of variance , LSD , Least-significant difference , DAPI , 4′,6-diamidino-2-phenylindole , SPSS , Statistical product and service solutions , IF , Interaction factor , ROS , Reactive oxygen species , NDI , Nuclear division index , OECD , Organization for economic cooperation and development , HPRT , Hypoxanthine phosphoribosyl transferase , DHE , Dihydroethidine , MMR , Mismatch repair , NHR , Non-homologous recombination repair , BER , Base excision repair , NER , Nucleic acid excision repair , HR , Homologous recombination repair , DDR , DNA damage response , NOECs , No observed effect concentrations , NAC , N-acetyl-cysteine , ER , Endoplasmic reticulum